Inner ear lesions result in permanent deficiencies in balance and hearing. It is therefore important to reduce or eliminate the lesions that are accompanied by a variety of insults to the inner ear. Neurotrophic factors have been shown to protect inner ear structure and function against acoustic and ototoxic trauma. One neurotrophic factor, the Glial cell-line derived neurotrophic factor (GDNF) demonstrated a robust protective effect against trauma in the inner ear of the guinea pig. The experiments in this grant are designed to continue to characterize the protective effect of GDNF in the auditory and vestibular systems, and to extend the data to a different animal model, the mouse. The experiments will use gene transfer technology for GDNF transgene over-expression in the inner ear. Specifically, we propose to (a) determine the protective effect of GDNF on the mouse auditory and vestibular epithelia using electrophysiological, behavioral and morphological analyses, (b) determine the cells types that bind GDNF in normal and traumatized inner ear tissues and (c) shed light on the genes that are involved in the downstream signaling cascade of GDNF. The data we propose to generate will enhance our understanding of the mechanisms of action of GDNF in normal and injured inner ear epithelia, knowledge that may eventually lead to better clinical treatments